The First Prospective Human Evidence That Low Numbers of Circulating Endothelial Precursor Cells Predict Future Cardiovascular Events—Evidence of Defective Vascular Repair?
Authors: C. Schmidt-Lucke, L. Ro[Combining Diaeresis]ssig, S. Fichtlscherer, M. Vasa, M. Britten, U. Ka[Combining Diaeresis]mper, S. Dimmeler, A.M. Zeiher
Journal: Journal of the American Society of Nephrology (2005)

Ever since the seminal review of Russell Ross (1), the atherosclerotic plaque has been regarded as a highly dynamic lesion exhibiting inflammatory activity (2) as postulated by R. Virchow in 1856 (3). Although originally it had been thought that progression—and potential reversal—of the plaque was brought about by residential cells, it has recently been increasingly recognized that circulating, bone marrow–derived, mononuclear, endothelial precursor cells (4–7) participate in endothelial, and hence vascular, repair. These circulating progenitor cells express specific markers, e.g., CD34+KDR+, which allow their identification using standardized techniques (8), i.e., flow cytometry and in vitro culture using morphologic characteristics or expression of marker molecules as a read-out. Poorly characterized signals allow such precursors to specifically home in on sites of endothelial lesions and denudation (9–11), where they operate apparently not only by local proliferation, but, more importantly, by secreting cytokines and other factors, thus providing a micromilieu favoring repair. In apparently healthy subjects without manifest atherosclerosis, the number and, according to preliminary studies (12), the function of endothelial precursor cells correlate to the number of cardiovascular risk factors (13,14). Furthermore, a correlation exists between the number of endothelial precursor cells and endothelial dysfunction (13,15–17). What had been lacking so far was prospective, controlled evidence that a diminished number of endothelial precursor cells indeed predicted hard endpoints, e.g., the occurrence of cardiovascular events, thus providing some indirect evidence for a potential causal role. In the recent study of Schmidt-Lucke et al. (12), 44 patients with stable coronary artery disease, 33 patients with acute coronary syndromes, and 43 controls were followed for a median period of 10 mo. At baseline the authors measured circulating endothelial precursor cells as defined by expression of the surface marker CD34+KDR+ using flow cytometry. Cardiovascular events were defined as cardiovascular death, unstable angina, myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG), or ischemic stroke. The number of endothelial precursor cells was significantly lower in patients developing cardiovascular events (0.0067 ± 0.0097 per 100 peripheral mononuclear cells versus 0.02 ± 0.02 in patients without events). By Kaplan-Meier analysis, reduced numbers of endothelial precursor cells were associated with a significantly higher incidence of cardiovascular events (P < 0.0009). By multivariate analysis, reduced numbers of endothelial precursor cells were significant independent predictors of adverse prognosis, even when the data were corrected for traditional cardiovascular risk factors and disease activity (hazard ratio, 3.9). The remarkable results document that low numbers of endothelial precursor cells are strong, independent predictors of atherosclerotic events. This finding provides strong support for the hypothesis that these cells contribute to ongoing vascular repair. Indeed, recent experimental studies documented endothelial precursor cells homing into arterial segments denuded of endothelial cells after balloon injury (9,10), and they may even replace dysfunctional endothelial cells. Whether endothelial cell precursors are beneficial only by their action on plaque remodeling or whether effects on vasodilatation (13) and coronary collateral support (18) also play a role is currently undecided. The mechanism causing reduced numbers of endothelial cell precursors is currently unknown, but exhaustion of the cell pool in the bone marrow, impeded mobilization, or reduced survival and maturation in the circulation are potential explanations. In view of the fact that uremia can be regarded as a form of premature, accelerated aging (19), it is of interest that the capacity to react to stress-induced mobilization of precursor cells declines with increasing age (20). This has also been specifically shown in the atherosclerosis model of the apoE knockout mouse (21), a model that has been widely used to study accelerated atherogenesis in uremia (22–24). Why are the above findings of interest to nephrologists? In a seminal report, Lindner et al. (25) reported excess cardiovascular death in the dialyzed patient and postulated that in uremia atherosclerosis was accelerated. It had remained uncertain for a considerable time, however, whether excess cardiac death is not simply explained by the high prevalence of classic risk factors or whether truly uremia-specific acceleration of atherosclerosis occurs. This issue has meanwhile been settled by the demonstration of accelerated plaque growth in apoE knockout mice with reduced renal function (22–24), and even accelerated coronary calcification is suggested by studies in patients with early renal disease (26). Are there abnormalities of endothelial precursor cells in uremia (27)? Uremia with or without hemodialysis is associated with a deficient number of endothelial progenitor cells (28–30). After renal transplantation, numbers were decreased when the graft function was not normal (31). The capability of endothelial progenitor cells to migrate and form tubes was reduced, and the serum of uremic patients inhibited their capacity to differentiate in vitro. Amelioration of uremia after institution of renal replacement therapy increased their number (28). Are there perspectives for intervention to repair these defects? Several interventions increase endothelial precursor cells. In nonuremic patients it has been shown that physical training increases their number (32), and the same has been shown for statins (33–35) and for angiotensin receptor blockers (36). Finally, erythropoietin (EPO) has been identified as a potent physiologic stimulus of endothelial progenitor cell mobilization (37,38). These beneficial effects are not restricted to nonuremic patients. Even at concentrations that were subtherapeutic with respect to correction of anemia, EPO regulated endothelial progenitor cell concentrations (39). On the one hand, endothelial cells, presumably sloughing off the vascular wall, can be demonstrated in the circulation of uremic patients (40) and are associated with future vascular events (41). On the other hand, the numbers of the endothelial cell progenitor cells are diminished (28). These cells predict cardiovascular events, at least in nonuremic patients (12). It is not unreasonable to assume that the balance between vessel injury and repair is deranged in uremia. The above possibilities of intervention on the horizon give cause for cautious optimism.